1 s2.0 S2225411018304358 Main

Long-term use of Chinese herbal medicine therapy reduced the risk of asthma
hospitalization in school-age children: A nationwide population-based cohort study in

Taiwan
Pei-Chia Lo a , b,1, Shun-Ku Lin b , c, d, 1, Jung-Nien Lai b , e, f, *
a
Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, No.155, Sec.2, Linong St, Beitou Dist, Taipei City, Taiwan b Taiwan Association for
Traditional Chinese Medicine of Family, 9F, No.105, Yusheng St, Shilin Dist, Taipei City, Taiwan c Institute of Public Health, National Yang-Ming University, No.155, Sec.2, Linong
St, Beitou Dist, Taipei City, Taiwan d Department of Chinese Medicine, Taipei City Hospital, Renai Branch, No.10, Sec.4, Renai Rd, Daan Dist, Taipei City, Taiwan e School of
Chinese Medicine, College of Chinese Medicine, China Medical University, No.91 Hsueh-Shih Road, North Dist, Taichung, Taiwan f Department of Chinese Medicine, China Medical
University Hospital, No.2, Yude Rd, Taichung City, Taiwan

articleinfo
eceived 23 August 2018 Received in revised form 10 April 2019 Accepted 21 April 2019 Available online xxx
Article history: R
Keywords: A sthma Childhood asthma Traditional Chinese medicine Chinese herbal medicine National health insurance research database (NHIRD)
abstract
Background: C linical trials have indicated some traditional Chinese medicine formulas reduce airway hyperresponsiveness and relieve asthma symptoms. This
study investigated Chinese herbal Medicine (CHM) for childhood asthma and clarified the relationship between CHM use and consequent asthma hospitalization
by a population-based cohort study. Methods: We used the data of one million individuals randomly selected from Registry of Beneficiaries of the National Health
Insurance Research Database. Patients aged less than 18 years and diagnosed as asthma were followed from 2000 to 2012 and divided into the CHM group and the
non-CHM group. Cox proportional hazard regression model was conducted to estimate the adjusted hazard ratio (aHR) of the two groups, and the Kaplan-Meier
survival curve was used to determine the association between CHM cumulative days and consequent asthma hospitalization. Results: O f the total of 33,865
patients, 14,783 (43.6%) were included in the CHM group, and 19,082 (56.4%) were included in the non-CHM group. After adjustment for gender, age,
comorbidities, and total numbers of asthma medication, CHM users had a lower risk of asthma hospitalization than non-CHM users (aHR: 0.90, 95% confidence
interval [CI]: 0.83e0.95). Children older than 6 years who used CHM therapy for more than 180 days exhibited a reduction of 29% for the risk of consequent
asthma hospitalization (aHR: 0.71, 95% CI: 0.51e0.98). Conclusion: Children aged 6e18 years who used more than 6 months CHM therapy reduced the risk of
consequent asthma hospitalization. Long-term CHM therapy has benefit in school-age children with asthma. © 2019 Center for Food and Biomolecules, National
Taiwan University. Production and hosting by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
1. Introduction
Asthma is a common respiratory diseases worldwide and is the
leading cause of repetitive or prolonged cough, wheezing even shortness of breath in children. According to the national statistics in Taiwan, the
prevalence of childhood asthma has increased each year. One study reported that the 8 years asthma prevalence in children and adolescents in
2000e2007 was 15.7%,1 another re-
* Corresponding author. School of Chinese Medicine, China Medical University, No.91 Hsueh-Shih Road, Taichung, 40402, Taiwan.
E-mail addresses: r inko0207@gmail.com (P.-C. Lo), gigilaskl@gmail.com
ported that the childhood asthma prevalence was from 12.99% in 2002 to 16.86% in 2008, and the rate was still up to 15e20% in recent years.2
Besides, asthma is a major cause of hospital out- ( S.-K. Lin), ericlai111@gmail.com, jnlai@mail.cmu.edu.tw (J.-N. Lai).
patients visits and health-care expenditure in children, resulting in Peer review under responsibility of The Center for Food and Biomolecules,
2.2efold higher than non-asthmatic children.3 Despite consider- National Taiwan University.
1
These authors contributed equally to this work.
able improvement of asthma medications and the management
Journal of Traditional and Complementary Medicine xxx (xxxx) xxx
Please cite this article as: Lo P-C et al., Long-term use of Chinese herbal medicine therapy reduced the risk of asthma hospitalization in school-
age children: A nationwide population-based cohort study in Taiwan, Journal of Traditional and Complementary Medicine, https://doi.org/
10.1016/j.jtcme.2019.04.005
Contents lists available at ScienceDirect
Journal of Traditional and Complementary Medicine

journal homepage: http://www.elsevier.com/locate/jtcme
https://doi.org/10.1016/j.jtcme.2019.04.005 2225-4110/© 2019 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC. This
is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
P.-C. 2 Lo et al. / Journal of Traditional and Complementary Medicine xxx (xxxx) xxx Please
cite this article as: Lo P-C et al., Long-term use of Chinese herbal
medicine therapy reduced the risk of asthma hospitalization in school- age

children: A nationwide population-based cohort study in Taiwan,
Journal of Traditional and Complementary Medicine, https://doi.org/ 10.1016/j.jtcme.2019.04.005 strategy of health education, the prevalence and
healthcare burden
asthma, those without complete insurance data (n = 1 411) and of asthma still appear to be increasing.4 According to the Global
those diagnosed with asthma before the end of 1999 (n = 10,580) Initiative for Asthma (GINA) guidelines, conventional antiasthmatic
were excluded. Moreover, to ensure that all patients had asthma, drugs, including controllers and relievers, are the standard treat-
those without any antiasthmatic medication prescription record ment for asthma.5 Antiasthmatic drugs have been the predominant
(n = 252) were excluded. The antiasthmatic medications recom- treatment for childhood asthma for many years; however, parents
mended in the GINA guidelines, including controllers (inhaled of some children with asthma have opted for other types of therapy
corticosteroids, long-acting b2 agonist, mast-cell stabiliser, anti- such as complementary and alternative therapies because of con-
leukotriene, anti-IgE monoclonal antibody) and relievers (short- cerning the side effect of the corticosteroids.6 Among these treat-
acting b2 agonist and short-acting anticholinergics). ments, the most common alternative or complementary therapies for childhood asthma are
traditional Chinese medicine (TCM)
2.3. CHM exposure and follow-up period t herapies such as Chinese herbal medicine (CHM) and acupuncture.6,7 Clinical trials have indicated
that some CHM formulas
A total of 33,865 children met the inclusion criteria and were reduce airway hyperresponsiveness and relieve asthma
divided into two groups by the medical records of CHM use: the symptoms.8e10 However, insufficient evidence is available for the
CHM group (CHM use for more than 30 cumulative days) and the beneficial effects of long-term use of CHM for childhood asthma.11
non-CHM (CHM use for less than 30 cumulative days or no CHM The National Health Insurance (NHI) programme of Taiwan
use). In Taiwan, the CHM prescriptions reimbursed by the NHI established in 1996, provides comprehensive health insurance to all
programme only include TCM formulas or single herb in a residents of Taiwan. The claims data of the enrolees of the NHI
concentrated powder or granule form.7 programme collected over 20 years are compiled in the National
In the present study, we included all eligible patients in the Health Insurance Research Database (NHIRD), which serves as a
LHID for analysis without any sampling; besides, our study also valuable research resource.12 In particular, TCM therapy is covered
used an intent-to-treat analysis method that we fixed the group by the NHI programme of Taiwan, which is the only country
according to the patient's treatment, and no patient will change worldwide that possesses a large amount of TCM medical records
during the tracking period. Patients were followed from the first for more than 20 million people.13,14 To date, some descriptive
date of asthma diagnosis to the first asthma hospitalization or studies have used the NHIRD to analyse the utilization of TCM for
the last medical records before December 31, 2012. Asthma childhood asthma and have investigated the characteristics of TCM
hospitalization was defined by the identification of the ICD-9-CM users and the most commonly prescribed CHM formulas and single
code 493 in the admission diagnosis record. For each patient, we herbs.15e18 However, there is still no large-scale study evaluating
calculated the exposure of CHM during the follow-up period. the long-term efficacy of CHM on childhood asthma. The aim of the
And we also stratified the study population into 0e5 years and study is to investigate CHM therapy for childhood asthma and
6e18 years old to distinguish preschool age children from school clarify the relationship between CHM use and consequent asthma
age children. The study design and flow chart are illustrated in hospitalization.
Fig. 1.
2. Material and methods
2.4. Study variables
2.1. Study design and data resource
Demographic characteristics, including gender, age, and insured region, of children with asthma in the two groups were demon- This retrospective
cohort study was conducted using the Lon-
strated based on previous studies.5 GINA published guidelines gitudinal Health Insurance Database 2005 (LHID 2005), a data of
addressing the treatment of asthma in children younger than 5 NHIRD released from the National Health Research Institutes.
years, and previous studies have reported that the pathogenesis of LHID2005 is a medical data of one million people randomly
early childhood asthma is different from that of later childhood sampled from all of the insurance population in Taiwan, and the
asthma.20,21 Therefore, the children in this study were stratified National Health Research Institutes claimed there is no significant
into the age groups of 0e5 years and 6e18 years old. The insured difference in age or gender between the sample in the LHID data-
region was categorised into seven administrative areas, namely base and the original insured population.19 LHID 2005 contained
Taipei City, Kaohsiung City, Northern Taiwan, Central Taiwan, patients' data and medical records, including patients’ gender,
Eastern Taiwan, Southern Taiwan, and outlying islands. Each region, birthdate, insured region, date of service, diagnosis, medication,
which represent the living area of the patients, has different treatment, expenditures, date of outpatient department (OPD) visit,
geographical environment and air quality. The type of anti- date of emergency department visit, and date of hospitalization
asthmatic drug and comorbidities were also identified in our study. from 2000 to 2012.19 From 1996 to the present day, the coverage of
The GINA guidelines recommend stepwise treatment as the stan- NHI is up to 99.6% of total population. All the identification
dard treatment for asthma, which implies that more types of numbers are encrypted to protect patient privacy, and the study
antiasthmatic drugs should be prescribed for more severe protocol was approved by the Institutional Review Board of Taipei
asthma.22 In our study, the total number of antiasthmatic drugs City Hospital, Taiwan (Case Number TCHIRB-10512111-E).
represents asthma severity. Furthermore, the comorbidities that often accompany asthma, including allergic rhinitis, bronchitis, 2.2. Study
population
acute sinusitis, atopic dermatitis, gastroesophageal reflux disease, and urticaria, were also identified using the ICD-9-CM code and This
retrospective cohort study used the LHID2005 without any
were listed as our variables in our analyses.23e25 randomization, all the study population were detailed in Fig. 1. In this study, the inclusion criteria
were children aged less than 18
2.5. Statistical analyses years who were diagnosed with asthma (identified using the In- ternational Classification of Disease, Ninth Revision,
Clinical
The demographic characteristics of CHM users and non-CHM Modification [ICD-9-CM] code 493) and those with more than three
users were analysed using a logistic regression model to estimate OPD visits. To ensure that all children were newly diagnosed with
the adjusted odds ratio (aOR). The frequency distribution of TCM
P.-C. Lo et al. / Journal of Traditional and Complementary Medicine xxx (xxxx) xxx 3
Fig. 1. Flow chart of recruitment of subjects from the one million individuals randomly sampled from the National Health Insurance Research Database (NHIRD) from 2000 to 2012 in Taiwan.
80 days to analyse the
doseeresponse effect (Table 6). All statistical analyses were per- formed using
SAS, version 9.4(SAS Institute Inc., Cary, NC, USA). P < 0.05 was considered
OPD visits (identified using the ICD-9-CM code) of children with asthma was
statistically significant and calculated against 95% CIs.
analysed, and the frequency of visits for CHM therapy and
acupuncture/manipulation therapy were calculated separately in Table 2. The most
commonly prescribed TCM formula and the average dosage for children with 3. Results
asthma were estimated, and the average dose of Ma-Huang (Ephedrae herba) in
CHM by person-day was also calculated in our study (Table 3). A Cox proportional In the descriptive statistical analysis (Table 1), of the total of 33,865
regression model was used to estimate adjusted hazard ratio (aHR) with 95% patients, 14,783 (43.6%) were included in the CHM group, and 19,082 (56.4%)
confidence interval (95% CI) to determine the different risk factors for asthma were included in the non-CHM group. The demographic characteristics indicated
hospitalization (Table 5). that CHM users tended to be female, >6 years of age, and living in Central Taiwan,
To examine the relationship between CHM use and asthma Southern Taiwan, and Kaohsiung City in comparison with non-CHM users.
hospitalization, the cumulative days for which children with asthma were Regarding asthma medication use, CHM users tended to use more
prescribed CHM were stratified into 0 days, 1e30 days, 31e90 days, 91e180, and
Please cite this article as: Lo P-C et al., Long-term use of Chinese herbal medicine therapy reduced the risk of asthma hospitalization in school- age children: A
nationwide population-based cohort study in Taiwan, Journal of Traditional and Complementary Medicine, https://doi.org/ 10.1016/j.jtcme.2019.04.005
P.-C. 4 Lo et al. / Journal of Traditional and Complementary Medicine xxx (xxxx) xxx Table 1 Demographic characteristics for Chinese herbal medicine use among children with
asthma in Taiwan.
Characteristics Total No.(%) CHM users No.(%) Non-CHM Users, No.(%) CHM users/CHM nonusers aOR (95%CI)
Number of patients 33,865 (100%) 14,783 (43.6%) 19,082 (56.4%) Number of asthma hospitalization 3391 (10.0%) 1445 (9.8%) 1946 (10.2%) Gender
Male 19,346 (57.1%) 8228 (55.7%) 11,118 (58.3%) 1.00 Female 14,519 (42.9%) 6555 (44.3%) 7964 (41.7%) 1.12 (1.07e 1.17) Age at diagnosis (years)
0-5 26,319 (77.7%) 10,728 (72.6%) 15,591 (81.7%) 1.00 6-18 7546 (22.3%) 4055 (27.4%) 3491 (18.3%) 2.03 (1.92e 2.15) Insured region
Taipei city 7072 (20.9%) 2948 (19.9%) 4124 (21.6%) 1.00 Kaohsiung city 1503 (4.4%) 695 (4.7%) 808 (4.2%) 1.18 (1.05e 1.32) Northern Taiwan 12,248 (36.2%) 4746 (32.1%) 7502
(39.3%) 0.90 (0.85e 0.96) Central Taiwan 5614 (16.6%) 2946 (19.9%) 2668 (14.0%) 1.59 (1.48e 1.70) Southern Taiwan 6523 (19.3%) 3135 (21.2%) 3388 (17.8%) 1.34 (1.25e 1.44)
Eastern Taiwan 720 (2.1%) 272 (1.8%) 448 (2.4%) 0.88 (0.75e 1.04) Outlying islands 185 (0.6%) 41 (0.3%) 144 (0.8%) 0.41 (0.29e 0.59) Total number of asthma medication a
1 1266 (3.7%) 537 (3.6%) 729 (3.8%) 1.00 2 3593 (10.6%) 1494 (10.1%) 2099 (11.0%) 1.03 (0.90e 1.18) 3 7498 (22.1%) 3007 (20.3%) 4491 (23.5%) 1.07 (0.94e 1.22) 4 11,539
(34.1%) 4916 (33.3%) 6623 (34.7%) 1.26 (1.10e 1.44) S 5 9969 (29.4%) 4829 (32.7%) 5140 (26.9%) 1.65 (1.44e 1.90) Total number of comorbiditiesb
1 36 (0.1%) 5 (0.03%) 31 (0.2%) 1.00 2 353 (1.0%) 98 (0.7%) 255 (1.3%) 2.40 (0.90e 6.38) 3 2134 (6.3%) 653 (4.4%) 1481 (7.8%) 3.08 (1.19e 7.99) 4 9827 (29.0%) 4109 (27.8%)
5718 (30.0%) 5.36 (2.07e 13.86) S 5 21,514 (63.5%) 9918 (67.1%) 11,596 (60.8%) 6.73 (2.60e 17.42)
Abbreviations: CHM, Chinese herbal medicine; aOR, adjusted odds ratio; Cl, confidence interval.
Asthma medication including:short-acting b2 agonists, short-acting anticholinergics, inhaled glucocorticosteroids, long-acting b2 agonists,antileukotriene, mast-cell stabilizers,
a
anti-IgE monoclonal antibody.
b
Comorbidities including:allergic rhinitis, acute upper respiratory infection, acute bronchitis, acute sinusitis, atopic dermatitis, gastroesophageal reflux disease, urticaria.
types of conventional antiasthmatic drugs in comparison with non-
higher than that of non-CHM users (aOR: 6.73, 95% CI: 2.60e17.42). CHM users. The proportion of the CHM group that used more than
On the basis of the frequency distribution of TCM outpatient five types of asthma medication was 1.65-fold higher than that of
visits in Table 2, children with asthma were mostly treated with the non-CHM group (aOR: 1.65, 95% CI: 1.44e1.90). CHM users also
CHM, rather than acupuncture or manipulation therapy. The ratio exhibited more comorbidities than non-CHM users. The proportion
of CHM therapy to acupuncture or manipulation therapy was 9:1. of CHM users with more than five comorbidities was 6.73-fold
Moreover, respiratory-related disease; symptoms, signs, and ill-
Table 2 Frequency distribution of traditional Chinese medicine OPD visits by major disease (ICD-9-CM code) in children with asthma from 2000 to 2012.
Major Disease Category Icd-9 Code Range Number of Visits (%)
Chinese Herbal Medicine Therapies
10.1016/j.jtcme.2019.04.005
Total of CHM
Infectious and Parasitic Diseases 001e 139 311 (0.07) 1 (0.00) 312 (0.06) Neoplasms 140e 239 429 (0.1) 5 (0.01) 434 (0.09) Endocrine, Nutritional, Blood and Metabolic Diseases,
and
Immunity Disorders
Acupuncture, or Manipulative Therapies
240e 289 2166 (0.5) 34 (0.07) 2200 (0.43)
Mental Disorders, Diseases of The Nervous System and Sense
Organs
290e 389 5968 (1.3) 767 (1.6) 6735 (1.32)
Diseases of The Circulatory System 390e 459 877 (0.2) 99 (0.2) 976 (0.19) Diseases of The Respiratory System 460e 519 258,557 (56.0) 502 (1.0) 259,059
(50.8) Diseases of The Digestive System 520e 579 45,207 (9.8) 84 (0.2) 45,291 (8.9) Diseases of The Genitourinary System 580e 679 17,871 (3.9) 26 (0.05) 17,897 (3.5) Diseases of
The Skin And Subcutaneous Tissue 680e 709 22,903 (5.0) 67 (0.1) 22,970 (4.5) Diseases of The Musculoskeletal System and Connective Tissue
710e 739 4529 (1.0) 8200 (17.0) 12,729 (2.5)
Symptoms, Signs, and Ill-Defined Conditions
780e 799 100,051 (21.7) 205 (0.4) 100,256
(19.7) Injury and Poisoning 800e 999 2355 (0.5) 38,074 (79.1) 40,429 (7.9) Supplementary Classification V01e V82, E800-
E999
11 (0.00) 0 (0.0) 11 (0.0)
Others 740e 779 412 (0.1) 70 (0.15) 482 (0.1) Total 461,647 (90.6) 48,134 (9.4) 509,781
(100.0)
Table 3 Most commonly prescribedtraditional Chinese medicine formulas forchildren with asthma in Taiwanfrom 2000 to 2012.
Herbal formula (Pin-yin name)
10.1016/j.jtcme.2019.04.005
Ma-Huang dose/day
Xin-Yi-Qing-Fei-
Tang
Ingredients of herbal formula Pin-yin name (Official name) N (%) Average
dosage/day
2.6 g
Xiao-Qing-Long-
Tang
Xin-Yin (MagnoliaeFlos); Bai-He (LiliiBulbus); Zhi- Mu (AnemarrhenaRhizoma); Shi-Gao(GypsumFibrosum); Pi-
54034 Pa-Ye (EriobotryaeFolium); Sheng-Ma (CimicifugaeRhizoma); Mai-men-dong (Ophiopogonis Radix); Zhi-Zi
(6.03) (GardeniaeFructus); Huang-Qin (Scutellariae Radix); Gan-Cao (Glycyrrhizae Radix)
2.4 g 0.5 g
Ma-Xing-Gan-Shi-
Tang
Ma-Huang (EphedraeHerba); Gui-Zhi (CinnamomiRamulus); Bai-Shao (Paeoniae Alba Radix); Gan-Cao
44912 (Glycyrrhizae Radix); Gan-Jiang (ZingiberisRhizoma); Xi-Xin (Asari Radix Rhizoma); Ban-Xia
(5.01) (PinelliaeRhizoma); Wu-Wei-Zi (SchisandraeFructus) Ma-Huang (EphedraeHerba); Ku-Xing-Ren (ArmeniacaeAmarum Semen); Gan-Cao (Glycyrrhizae Radix); Shi-
37080
2.8 g 1.0 g Gao (GypsumFibrosum)
(4.14) Cang-Er-San Cang-Er-Zi (XanthiiFructus); Xin-Yin (MagnoliaeFlos); Bai-Zhi (AngelicaeDahuricae Radix); Bo-He
2.5 g (MenthaeHerba) Xin-Yi-San Xin-Yin (MagnoliaeFlos); Bai-Zhi (AngelicaeDahuricae Radix); Sheng-Ma (CimicifugaeRhizoma); Gao-Ben
(LigusticiRhizoma et Radix); Fang-Feng (Saposhnikoviae Radix); ChuanXiong (Chuanxiong Rhizoma); Xi-Xin (Asari Radix et Rhizoma); Chuan-Mu-Tong (Clematidis Caulis);
Gan-Cao (Glycyrrhizae Radix)
36979 (4.13)
2.4 g
Yin-Qiao-San Jin-Yin Hua (LoniceraeFlos); Lian-Qiao (ForsythiaeFructus); Jing-Jie (SchizonepetaeHerba); Dan-Dou-Chi (Sojae Semen Preparatum); Jie-Geng (Platycodi Radix);
Bo-He (MenthaeHerba); Niu-Bang-Zi (ArctiiFructus); Gan-Cao (Glycyrrhizae Radix); Dan-Zhu-Ye (Lophatheri Caulis Folium); Lu-Gen (PhragmitisRhizoma)
35815 (4)
2.8 g
Ge-Gen-Tang Ge-Gen (Puerariae Radix); Ma-Huang (EphedraeHerba); Gan-Jiang (ZingiberisRhizoma); Gui-Zhi
(CinnamomiRamulus); Bai-Shao (Paeoniae Alba Radix); Gan-Cao (Glycyrrhizae Radix); Da-Zao (JujubaeFructus)
25134 (2.81)
2.6 g 0.5 g
Xing-Su-San Zi-Su-Ye (Perillae Folium); Jie-Geng (Platycodi Radix); Da-Zao (JujubaeFructus); Ban-Xia (PinelliaeRhizoma);
Zhi-Ke (CitriImmaturusFructus); Ju-Pi (CitriReticulataePericarpium); Fu-Ling (Poria); Gan-Cao (Glycyrrhizae Radix); Ku-Xing-Ren (ArmeniacaeAmarum Semen); Qian-Hu
(Peucedani Radix); Gan-Jiang (ZingiberisRhizoma)
23701 (2.65)
2.9 g
Zhi-Sou-San Jie-Geng (Platycodi Radix); Jing-Jie (SchizonepetaeHerba); Zi-Wan (Asteris Radix et Rhizoma); Bai-Bu
(Stemonae Radix.); Bai-Qian (CynanchiStauntoniiRhizoma et Radix); Gan-Cao (Glycyrrhizae Radix); Ju-Pi (CitriReticulataePericarpium)
21641 (2.42)
2.7 g
Ding-Chuan-Tang Ma-Huang (EphedraeHerba); Sang-Bai-Pi (Mori Radicis Cortex); Bai-Guo (Ginkgo Semen); Huang-Qin
(Scutellariae Radix); Zi-Su-Zi (PerillaeFructus); Ku-Xing-Ren (ArmeniacaeAmarum Semen); Ban-Xia (PinelliaeRhizoma); Kuan-Dong-Hua (FarfaraeFlos); Gan-Cao (Glycyrrhizae
Radix)
17960 (2.01)
2.7 g 0.4 g
Table 4 Mechanism and therapeutic effect of frequently prescribed TCM formulas for children with asthma in Taiwan.
Herbal formula (Pin-yin name)
17657 (1.97)
Function in TCM theory Mechanism or therapeutic effect
Xin-Yi-Qing-Fei-
Tang
Clears lung heat, relieves stuffy nose
Xiao-Qing-Long-
Tang
Regulation of T-cell by activation of theCD8+ cells and double-negative T-cell population in the lung (animal model)32 Suppressed the increase of eosinophils in the airway,
stimulation of b2-adrenoceptors leading to bronchial relaxation (animal model)40 Ma-Xing-Gan-Shi-
Tang
Dispels the exterior wind cold, warms lung rheum
Clears lung heat, suppress cough Stimulation of b2-adrenoceptors on bronchial smooth muscle and inhibiting the neutrophil into the airway
(animal model)33 Inhibitory activity against different strains of human influenza A viruses (in vitro)41 Cang-Er-San Dispels the wind, relieves stuffynose Suppression of thromboxane
B2, eosinophil infiltration, and endothelial nitric oxide synthase in the nasal
tissues (animal model)42 Relieved symptoms of nasal congestion among patients with perennial allergic rhinitis (clinical trial) Xin-Yi-San Dispels the wind cold, relieves stuffy
nose
Reduction of nasal airflow resistance, suppression of serum IgE levels and increased production of IL-10, sICAM-1, and IL-8 in patient with perennial allergic rhinitis (clinical trial)43
Yin-Qiao-San Clears heat and resolving toxin Relief fever and well-tolerated in patient with paracetamol and ibuprofen hypersensitivity.(clinical trial)44 Ge-Gen-Tang Resolves
exterior cold with sweating Stimulates mucosalcells to secrete IFN-b to counteract viral infection, against human respiratory syncytial
virus inhuman respiratory tract cell lines (in vitro)45 Xing-Su-San Diffuses lung and transforming phlegm Zhi-Sou-San Suppress cough Ding-Chuan-Tang Suppress cough and wheeze,
diffuses
lung and clearing lung heat
Suppressed the eosinophil infiltration into lung tissue, and inhibited the antigen induced immediate asthmatic responses (animal model)46 Improving airway hyper-responsiveness,
symptoms for asthma children (clinical trial)8
defined disease; and digestive-related disease were the most
person/day after conversion. To determine the different risk factors common diseases treated using CHM therapy. Table 3 shows the
for asthma hospitalization, we analysed the adjusted hazard ratio most commonly prescribed TCM formulas for children with
(aHR) of each demographic variable (Table 5). Patients younger asthma. X in-Yi-Qing-Fe-Tang, Xiao-qing-long-tang, and Ma-Xing-
than 6 years and those using multiple types of asthma medications Gan-Shi-Tang were the top three TCM formulas prescribed to chil-
were at a high risk of asthma hospitalization. Notably, children with dren with asthma. The average dosage was less than 3.0 g person/
asthma using more types of asthma medication exhibited a higher day in each TCM formula. Among the top 10 TCM formulas, Xiao-
risk of asthma hospitalization (S5 asthma medications: aHR: 10.37, qing-long-tang, Ma-Xing-Gan-Shi- Tang, Ge-Gen-Tang, a nd Ding-
95% CI: 6.57e16.35). After adjustment for gender, age, comorbid- Chuan-Tang c ontained the Ma-Huang c ompound. Although the
ities, and total numbers of asthma medication, CHM users had a proportion of Ma-Huang d iffered in different TCM formulas, the
lower risk of asthma hospitalization than non-CHM users (aHR: average dose of Ma-Huang i n each TCM formula was less than 1.0 g
0.90, 95% CI: 0.83e0.95). As shown in Table 6 and F ig. 2, more CHM
P.-C. 6 Lo et al. / Journal of Traditional and Complementary Medicine xxx (xxxx) xxx Table 5
Adjusted Cox proportional hazard model analyseswith 95% confidence interval for asthma hospitalization in children with asthma.
Variables Adjusted Hazard Ratioa 95% Confidence Interval p e
Value
Gender
Males reference Females 0.90 0.84e 0.96 Age at diagnosis
0e 5 years reference 6e 18 years 0.66 0.59e 0.74 <0.0001 Total number of comorbiditiesb
1 reference 2 0.98 0.13e 7.49 3 1.30 0.18e 9.29 4 1.29 0.18e 9.19 S 5 1.45 0.20e 10.35 Total number of asthma medicationc
1 reference 2 1.70 1.04e 2.77 0.0352 3 3.32 2.10e 5.27 <0.0001 4 5.05 3.20e 7.95 <0.0001 S 5 10.37 6.57e 16.35 <0.0001 CHM usage
No(< 30 days) reference Yes(S 30 days) 0.90 0.83e 0.95 0.0048
Abbreviations: CHM, Chinese herbal medicine.
a
adjusting all listed variables. b Comorbidities including:allergic rhinitis, acute upper respiratory infection, acute bronchitis, acute sinusitis, atopicdermatitis, gastroesophageal reflux
disease, urticaria.
Asthma medication including:short-acting b2 agonists, short-acting anticholinergics, inhaled glucocorticosteroids,long-actingb2 agonists, antileukotriene, mast- cell stabilizers,
c
anti-IgE monoclonal antibody.

Table 6 Number of asthma hospitalization cases, population-at-risk, and adjusted hazard ratios and 95% confidence intervals for asthma hospitalization estimated according to
different CHM cumulative days in children with asthma.
Variables No. Case/population Adjusted Hazard Ratioa 95% CI p e
Value
0e 5 years (N = 26,319) CHM usage (days)
0 947/8831 reference 1-30 637/5331 1.04 0.94e 1.15 31-90 583/5161 0.93 0.84e 1.04 91-180 358/3008 0.98 0.87e 1.11 >180 462/3988 0.93 0.83e 1.04 6e 18 years (N = 7546) CHM
usage (days)
0 86/1447 reference 1-30 84/1600 0.83 0.62e 1.13 31-90 107/1958 0.82 0.62e 1.09 91-180 59/1177 0.74 0.53e 1.03 >180 68/1364 0.71 0.51e 0.98 0.000149
Abbreviations: CHM, Chinese herbal medicine.
a
Adjusting gender, comorbidity, and asthma medication.
10.1016/j.jtcme.2019.04.005 cumulative days were associated with a lower risk of asthma hos-
with asthma and to investigate the integration of CHM with con- pitalization in patients aged 6e18 years. Moreover, children older
ventional antiasthmatic drugs in asthma treatment. We observed than 6 years who used CHM therapy for more than 180 days
that children prescribed antiasthmatic drugs were frequently CHM exhibited a reduction of 29% for the risk of consequent asthma
users in Taiwan. As shown in Fig. 1, from 2000 to 2012, 14,783 hospitalization (aHR: 0.71, 95% CI: 0.51e0.98) (see Table 4).
(43.6%) children with asthma had used CHM therapy, and children using CHM often tended to be females, older (6e18 years), and live
4. Discussion
in Central Taiwan. However, more than half of patients had not used CHM therapy, probably because it was not as convenient as inhaled
With the rapidly increasing healthcare expenditure in Taiwan, there are increasing concerns regarding the benefits and risks of the combination
antiasthmatic drugs with CHM. However, the verifi- cation and quantification of the research and public health impli- cations of these concerns
have been limited because of the absence of comprehensive information on exposure to the full range of CHM in children with asthma. According
to our literature review, this study is the first to use a random population-based cohort to study the correlation of CHM use with asthma
hospitalization in children
antiasthmatic drugs for younger children. The highest density of CHM users was located in Central Taiwan, and it probably because of most TCM
doctors was located in Central Taiwan.26 The GINA guidelines recommend stepwise treatment as the standard treatment for asthma, which
implies that more types of antiasthmatic drugs should be prescribed for more severe asthma. In our study, we discovered that CHM users were
prescribed more types of antiasthmatic drugs than non-CHM users, indicating that conventional antiasthmatic drugs did not succeed in
controlling asthma
ng and relieving the stuffy nose. Xiao-qing-long-tang ( XQLT)is suitable for
hma or allergic rhinitis combined with external cold and internal rheum, and it
rms the lung and suppresses cough or wheezing by the mechanism of regulation
T-cell by activation of theCD8+ cells in the lung and suppressed the increase of
sino- phils in the airway.29e32 Ma-Xing-Gan-Shi-Tang (MXGST) is specif- ically
escribed for heat-wheezing; it clears the heat of the lung and suppresses cough or
eezing,33 the possible mechanism of MXGST is to stimulate b2-adrenoceptors
bronchial smooth muscle and inhibit the neutrophil into the airway.33 Among the
p 10 TCM formulas, Xiao-qing-long-tang, Ma-Xing-Gan-Shi-Tang, Ge-
n-Tang, and Ding-Chuan-Tang contain the Ma-Huang composi- tion, which
ates the smooth muscle of bronchus and had been widely used for treating
hma in Europe and Japan before other antiasthmatic drugs developed.34
Generally, the purpose of CHM is to improve symptoms or to
treat the disease through physical adjustment or immunomodu- laiton,35 and
sometimes, medication has to be continually used for a longer time for treating
diseases, particularly chronic diseases or allergic diseases. Patients or their parents
may be concerned about the potential risk or adverse effects of the long-term use of
CHM.36 In our study, we discovered that children older than 6 years who used
CHM therapy lowers the risk of asthma hospitalization, particularly those using
CHM for more than 180 days. The result in coordinated with a previous
multicenter, double-blind and placebo-controlled study that CHM therapy for 6
months improved the clinical symptoms in children with asthma, espe- cially peak
expiratory flow rate (PEFR). The possible mechanism of CHM in that study
Fig. 2. Survival curve of asthma hospitalization in asthmatic children. Kaplan-Meier survival curves
and log-rank analyses revealed the rates of asthma hospitalization between different CHM cumulative including increasing total T cell and PGE2, decreasing B cell, LTC4, IFN-gamma
days (log-rank test, p < 0.001). and IL-410. Another clinical study discovered that formula contained
Mai-Men-Dong-Tang a nd Liu-Wei-Di-Huang Wan i n 5e20 years old children with
asthma for 6 months improved forced expiratory volume in 1s (FEV1) and
9
symptoms in some children, or they could not tolerate the adverse effects of inhibited the synthesis of the IgE. It seems that CHMs takes times to achieve the
antiasthmatic drugs, leading them to opt for TCM treatment. The present findings immunomodulatory effect via different mechanism. However, CHM may not exert
showed that nearly 6 of 10 children with asthma who developed at least five the same effect in children younger than 6 years of age. Younger children have an
comorbidities and those with multiple chronic allergic conditions were more likely immature immune system and lung development37 who are vulnerable groups and
to use CHM therapy than those without chronic disease. usually exhibit an average of 6e10 times of common cold every year.38
According to the distribution of diseases by TCM outpatient visits, Furthermore, upper airway infection caused by virus trig- gers approximately 80%
children with asthma opting for TCM treatment mostly exhibited respiratory-related of asthma exacerbation in children,20 and it probably explains why CHM exerts less
diseases. The main reason may be that a high proportion of patients with asthma effects in younger children.
concurrently experienced allergic rhinitis,23 and asthmatic symptoms are often Formulas containing Ma-Huang h ave been widely used for treating asthma
triggered by weather changes or upper airway infections.27,28 In our study, we or respiratory-related diseases in China since 3000 BCE.34 The effective
found that the top 10 TCM formulas were all prescribed for treating component of Ma-Huang (Ephedrae herba) is epinephrine and pseudoephedrine,
respiratory-related diseases. The most frequently prescribed TCM formulas were which dilating the respiratory smooth muscle quickly in asthma patients but
Xin-Yi-Qing-Fei-Tang, Xiao-qing-long- tang, and Ma-Xing-Gan-Shi-Tang ( Table
function as non- selective sympathetic stimulants on a and b receptors.34 Notably,
3). Xin-Yi-Qing-Fei-Tang is mostly frequently prescribed TCM formula for allergic
the adverse effects of ephedrine are weight-loss, insomnia, and dry mouth for a
rhinitis or sinusitis29,30; its mechanism of action involves clearing the heat of the
receptors and irregular tachycardia or cardiovascular effect for b 1 receptor.34,39 In
our study, the average dose of Ma- Huang i n each TCM formula was less than 1.0g
prescription days and frequency of the drugs, were retrospective, and we could not
person/day for children. However, some children may concurrently using long- determine whether patients had taken their prescribed CHM regularly. However, all
prescriptions were recommended on the basis of expert opinions. Therefore, the
acting b2 adrenoceptor agonists (LABA) and Ma-Huang r elated CHM. It suggested
that TCM physicians should evaluate the risk of adverse effects and follow upcompliance
the of children with asthma was assumed to be high. Third, owing to the
clinical reaction when prescribing Ma-Huang-related CHM to children with lack of actual clinical data, we could not draw any conclusions on the severity of
asthma. asthma symptoms in children. Therefore, we used the total number of antiasthmatic
drugs to represent asthma severity on the basis of the stepwise treatment
This present study has four limitations. First, this study did not include
recommended by GINA guidelines to realise the clinical situation to some extent.
some over-the-counter of CHM available in Taiwan, implying the frequency of
Four, the single herbedrug interaction between TCM therapy and conventional
CHM use might have been under- estimated. However, because the NHIRD system
asthma treatment was not obtained in this study. According to the literature review,
covers all prescriptions including mostly CHM by qualified TCM physicians after
the clinical efficacy of TCM formula is attributed to the synergistic effects of
careful examination and diagnosis, providing affordable, acces- sible, and
multiple herbs. On the other
convenient asthma healthcare, the likelihood of parents purchasing over-the-counter
CHM for their children is relatively low. Second, the medical records, including
Please cite this article as: Lo P-C et al., Long-term use of Chinese herbal medicine therapy reduced the risk of asthma hospitalization in school- age children: A
nationwide population-based cohort study in Taiwan, Journal of Traditional and Complementary Medicine, https://doi.org/ 10.1016/j.jtcme.2019.04.005
P.-C. 8Lo et al. / Journal of Traditional and Complementary Medicine xxx (xxxx) xxx hand, the clinical efficacy of a single herb of TCM is not attributed to a single
effect on one pathway, but to multiple effects.3. To date, some herbedrug interaction research in vivo or in vitro is available.39 However, few
studies have investigated the single herbedrug interaction among children with asthma because of the complexity.
5. Conclusions
Asthma is a chronic, airway-inflammatory disease, and often triggered by allergen. Except Ma-Huang ( Ephedrae herba) , other CHMs act as
anti-inflammatory, anti-allergic reaction or immunomodulatory effect via different mechanism in relieving asthma symptoms. In our large-scale
cohort study, we found that children aged 6e18 years who used more than 6 months CHM therapy reduced the risk of consequent asthma
hospitalization. Longeterm CHM therapy has benefit in school-age children with asthma. However, there was no association between CHM
therapy and asthma hospitalization in children younger than 6 years in the study. Recognizing the benefits of TCM and CHM therapy, exploring
its potential mechanism and herb-drug interaction may be beneficial to the overall health and quality of life of children with asthma.
Conflicts of interest
Authors declare that they have no conflict of interest.
Funding
This work was supported by the Department of Chinese Medi- cine and Pharmacy, Ministry of Health and Welfare [grant numbers:
MOHW105-CMAP-M-114-112415].
Acknowledgements
This research was based on a portion of data from the National Health Insurance Research Database, Taiwan. The interpretation and conclusion in
the study do not represent those of the National Health Insurance, Department of Health, or National Health Research Institutes.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jtcme.2019.04.005.
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Long-term use of Chinese herbal medicine therapy reduced the risk of asthma

hospitalization in school-age children: A nationwide population-based cohort study in

University Hospital, No.2, Yude Rd, Taichung City, Taiwan

Journal of Traditional and Complementary Medicine

medicine therapy reduced the risk of asthma hospitalization in school- age

anti-IgE monoclonal antibody.

anti-IgE monoclonal antibody.

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